Alpha-arylalkanoic acids are widely used as active anti-inflammatory, analgesic, and anti-pyretic pharmaceutical products. Such acids include, for example, ibuprofen, 2-(4-isobutylphenyl)propionic acid and fenoprofen, 2-(3-phenoxyphenyl)propionic acid. Various methods are known in the art for making these acids and their corresponding esters. For example, .alpha.-arylalkanoic esters can be made from corresponding carbonyl compounds of the general formula: ##STR3## wherein at least one of the R.sup.1 and R.sup.2 groups is an alkyl group and the other is a hydrogen atom or an alkyl group or wherein R.sup.1 is a bromine atom and R.sup.2 is an alkyl group (Journal Am. Chem. Soc., 95:3340 [1973]; Synthesis, p. 126, [1981]; Synthesis, p. 456, [1982]; Parkin Transactions (British Chem. Soc.), 1:235 [1982]; Tetrahedron Letters, 23:235 [1982], Tetrahedron Letters 22:4305 [1981]; Journal Organic Chemistry, 43:2936 [1978]; Chemical Communications, p. 1311, [1982].
Each of the aforementioned methods has at least one disadvantage, such as requiring the use of a poisonous thallium or lead salt or a precious, and expensive, silver salt, requiring a lengthy reaction time, and producing the desired product in low yields. Y. Tamura, Japanese Patent Publication No. Sho 59 [1984]-163,345, laid open Sept. 14, 1984, discloses a method of preparing .alpha.-arylalkanoic esters represented by the general formula ##STR4## wherein Ar.sup.1 is an aromatic hydrocarbon group, R and R.sup.1 each represent a hydrogen atom or an alkyl group, and R.sup.2 is an alkyl group, by reacting a compound of trivalent iodine having the general formula ##STR5## wherein Ar is an aromatic hydrocarbon group and X and Y are each a group which can be eliminated as an anion, with a carbonyl compound having the general formula ##STR6## wherein Ar.sup.1, R, and R.sup.1 are as defined above. As disclosed therein, the reaction is effected in the presence of an orthocarboxylic ester having the general formula ZC(OR.sup.2).sub.3, wherein R.sup.2 is an alkyl group and Z is a hydrogen atom or an alkyl group. According to the Tamura disclosure, the reaction can be completed smoothly within a short period of time via heating in the presence of concentrated sulfuric acid. Example 1 thereof discloses heating and agitating 1 mmole of p-isobutylpropiophenone and 1 mmol of iodobenzene diacetate in 1.5 ml (13.7 mmol) o-formic acid methyl ester in the presence of 1 mmole concentrated sulfuric acid for 30 minutes to obtain ibupurophene [sic] methyl ester. Similarly, synthesis of methyl 2-arylpropanoates (such as the methyl ester of ibuprofen) from aryl ethyl ketones (such as p-isobutylphenyl ethyl ketone, i.e. p-isobutylpropiophenone) using diacetoxyphenyliodine (also known as iodobenzene diacetate) wherein the reaction is performed in trimethyl orthoformate in the presence of sulfuric acid (10 mmol per 5 mmol of ketone in typical procedure) is disclosed by Tamura et al., Synthesis, March 1984, 231-232. Although the method of Tamura (and co-workers) appears to eliminate one or more disadvantages of methods disclosed in the older art, it neither recognizes nor overcomes the problems resulting from attempting to conduct the reaction in the presence of water, such as reduced yields of the arylalkanoic esters. Trivalent iodine compounds within the above formula, e.g. iodobenzene diacetate, are typically contaminated with water in amounts up to 10% as a result of their preparation in aqueous systems. Moreover, although such compounds may be dried via vacuum dessication (Sharefkin et al., Organic Syntheses, Coll. Vol. 5, 660-663 [1973] or oven drying, such methods are slow and tedious, while oven drying presents risks of explosion and loss of the iodine compound. Accordingly, there is a substantial need in the art for improvements in the above-described Tamura method, whereby the above-noted problems are at least substantially diminished.
The present invention recognizes the above-noted problems and fulfills the above need by providing a low-cost improvement in the Tamura method, wherein water-containing trivalent iodine compounds are chemically dried with anhydrides in the presence of the carbonyl compound or ketone, with essentially no loss in yield as would result from reaction of the anhydride with the ketone or the iodine compound and/or interraction between the ketone and the iodine compound.